WO2007006391A2 - Cynara scolymus extracts, the use thereof ans formulations containing them - Google Patents

Cynara scolymus extracts, the use thereof ans formulations containing them Download PDF

Info

Publication number
WO2007006391A2
WO2007006391A2 PCT/EP2006/005778 EP2006005778W WO2007006391A2 WO 2007006391 A2 WO2007006391 A2 WO 2007006391A2 EP 2006005778 W EP2006005778 W EP 2006005778W WO 2007006391 A2 WO2007006391 A2 WO 2007006391A2
Authority
WO
WIPO (PCT)
Prior art keywords
extracts
cynaropicrin
cynara scolymus
water
extract
Prior art date
Application number
PCT/EP2006/005778
Other languages
French (fr)
Other versions
WO2007006391A3 (en
Inventor
Ezio Bombardelli
Gabriele Fontana
Andrea Giori
Paolo Morazzoni
Massimo Ronchi
Sabrina Arpini
Original Assignee
Indena S.P.A.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Indena S.P.A. filed Critical Indena S.P.A.
Priority to EP06754391A priority Critical patent/EP1906983A2/en
Priority to JP2008520736A priority patent/JP2009501708A/en
Priority to US11/988,638 priority patent/US20090285911A1/en
Priority to CA002614796A priority patent/CA2614796A1/en
Priority to AU2006269035A priority patent/AU2006269035A1/en
Publication of WO2007006391A2 publication Critical patent/WO2007006391A2/en
Publication of WO2007006391A3 publication Critical patent/WO2007006391A3/en
Priority to NO20080198A priority patent/NO20080198L/en

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/28—Asteraceae or Compositae (Aster or Sunflower family), e.g. chamomile, feverfew, yarrow or echinacea
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/55—Linaceae (Flax family), e.g. Linum
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • the present invention relates to the preparation of an extract of Cynara scolymus thorny varieties obtainable by fractioning on a resin and to the process for its preparation.
  • the process of the invention allows to obtain an extract, starting from the aerial parts of the thorny varieties of Cynara scolymus, containing three classes of active principles, namely dicaffeoylquinic acids, luteolin and cynaropicrin glycosides, in a constant ratio. Cynaropicrin is stabilized by addition of precise amounts of sulfated amino acids or suitable thio-derivatives. These extracts have hypolipemizing, anti- dyspeptic and vascular anti-inflammatory activities. The extracts are mainly formulated in oils rich in ⁇ -3 and ⁇ -6 acids which enhance the vascular activity. Technological Background
  • Cynara scolymus active principles are potent antioxidant agents which are easily degraded when drying the vegetable material.
  • the preparation of the vegetable biomass is therefore crucial to obtain extracts with high content in active principles.
  • Cynaropicrin is a terpene having anti-inflammatory activity and mild hypocholesterolemizing action.
  • cynaropicrin is poorly stable and this is one of the reasons why this compound is not present in extracts and formulations.
  • the presence of this compound in the extracts is crucial, because bioavailable substances with anti-inflammatory action, that can modulate vascular inflammation (NFkB and reactive protein C) are particularly suitable for the prevention and therapy of arteriosclerosis and heart diseases. Disclosure of the invention
  • the present invention relates to novel extracts of Cynara scolymus thorny varieties, preferably Cynara scolymus var. Spinoso sardo or Cynara scolymus var. tema containing three classes of active principles, dicaffeoylquinic acids, luteolin and cynaropicrin glycosides, in constant ratios.
  • the present invention further relates to the process for the preparation of said extract.
  • sulfated amino acids preferably cysteine
  • the addition of sulfated amino acids, preferably cysteine, during the extraction step or the subsequent processes for the purification or concentration of the Cynara scolymus extracts provides final extracts still containing high concentrations of cynaropicrin, which remains stable in the therapeutical formulations.
  • the sulfated amino acids give rise to adducts which stabilize the sesquiterpene and promote its absorption. In the plasma, these adducts undergo exchange reaction with protein sulfhydryl groups thus restoring cynaropicrin specific activity.
  • An important therapeutical use of the extract of the invention concerns the treatment of irritable colon, a disease affecting up to 9% of western countries population.
  • the suggested anti-inflammatory action related to the modulation of NFkB, TNF- ⁇ and some interleukins can be one of the mechanisms involved in the alleviation of irritable colon symptoms.
  • Sesquiterpen-lactones also interact, either directly or indirectly, with central nervous system mediators involved in intestinal diseases.
  • the extract when the sulfated amino acids are not used as stabilizing agents during the extraction and/or concentration steps, the extract can be stabilized by addition of sulfated amino acids to the formulations.
  • the extracts are prepared using the aerial parts of the plant, including capitula which are the richer in dicaffeoylquinic acids part; leaves mainly contain flavonoids and all of the cynaropicrin.
  • the whole fresh or dehydrated plant preferably the fresh one
  • the whole fresh or dehydrated plant can be used, in fixed ratios between capitula and the remaining aerial part ranging from 20:80 to 40:60, preferably 30:70.
  • the preparation of the vegetable biomass is crucial to avoid degradation of active principles when drying the vegetable material.
  • the vegetable material can be frozen immediately after collection to decrease the action of the many oxidases and hydrolases naturally occurring in the plants.
  • the frozen biomass is ground at -30 0 C and immediately immersed in the extraction alcohol solvent, which completes the enzyme inactivation as well as the extraction of the active principles.
  • Water-alcohol solutions are used for extracting all of the active principles, preferably 70% solutions which provide the best ratio among the various components.
  • an amount of cysteine 10% higher than the stoichiometric amount of cynaropicrin is added to the solvent.
  • the resulting water-alcohol extracts are concentrated at low temperatures ranging from 25 to 55 0 C, preferably at 35°C, under water vacuum.
  • aqueous solution is filtered, the solvent and the undesired substances are removed, the resulting solution is concentrated under vacuum to a volume corresponding to that of the extracted vegetable material, and is subsequently purified on an adsorption resin, such as a polystyrene resin, Amberlite, duolite and XADl 180.
  • an adsorption resin such as a polystyrene resin, Amberlite, duolite and XADl 180.
  • the resin is thoroughly washed with water and the desired extract is eluted with 90% ethanol until exhaustion of the resin.
  • the resulting extract according to the present invention has a novel composition compared with the extracts of the prior art; it particularly has a cynaropicrin content > 5%, a ratio of caffeoylquinic acids to cynaropicrin ranging from 1 :0.2 to 1 :0.8, preferably 1:0.6, and a ratio of luteolin glycosides to cynaropicrin ranging from 20 to 60%, preferably 50%.
  • the extract of the invention was subjected to biological investigation in a series of pharmacological tests.
  • the extract of the invention induced a reduction in cholesterol and triglycerides of 40 and 35%, respectively, in the ethanol-induced hyperlipidemia test, and a dose-dependent reduction in the edema up to 75% in the carrageenin oedema test.
  • the choleretic action in the rat confirmed the data reported in literature.
  • the extract is well-suited for incorporation in pharmaceutical formulations such as tablets, sugar-coated pills, soft- and hard- gelatin capsules and cellulose capsules.
  • the extract will preferably be formulated in oils rich in ⁇ -3 and ⁇ -6 polyunsaturated acids such as Enothera biennis oil or Linum usitatissimum oil (flax oil).
  • Active dosages in humans range from 50 to 1000 mg daily, according to the severity of the disease to treat.
  • Example 1 Preparation of the extract of Cynara scolymus var. Spin osa
  • the water-alcohol eluate is concentrated, the content in cynaropicrin is checked by HPLC and L-cysteine dissolved in some water is added (in a 10% excess to the stoichiometric of cynaropicrin present). Further concentration and drying at 50 0 C under reduced pressure afford 49.4 g of purified dry extract (total caffeoylquinic acids HPLC content 15.1%, total flavonoids HPLC content 3.15%, total cynaropicrin HPLC content 7.64%).
  • Example 2 Preparation of the extract of Cynara scolymus var. tenia 4.12 kg of whole artichoke plant (capitula, stem and leaves) are extracted in a percolator with 70% ethanol at 70 0 C until complete extraction of the active principles. The cynaropicrin content in the combined extracts is determined, then L-cysteine is added in a 10% excess to the stoichiometric. The water-ethanol extract is concentrated under vacuum at a temperature not above 30 0 C. The aqueous concentrate is left to stand overnight at 4°C, then the solid residue, mainly consisting of chlorophyll and carotenoids, is decanted off.
  • the solution is filtered, then absorbed on a XAD 1180 resin which is subsequently washed with water until a complete removal of undesired insolubles.
  • the resin is washed with 90% ethanol and the eluate is concentrated to a 10% w/w residue, which is atomized to afford 40 g of an extract containing 15.8% caffeoylquinic acids, 4.2% luteolin glycosides and 8.6% cynaropicrin.
  • Example 5 Formulation of extract in oily suspension for soft-gelatin capsules
  • Example 8 Formulation of extract in oily suspension for soft-gelatin capsules

Landscapes

  • Health & Medical Sciences (AREA)
  • Natural Medicines & Medicinal Plants (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Microbiology (AREA)
  • Botany (AREA)
  • Biotechnology (AREA)
  • Alternative & Traditional Medicine (AREA)
  • Epidemiology (AREA)
  • Mycology (AREA)
  • Medical Informatics (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Diabetes (AREA)
  • Vascular Medicine (AREA)
  • Urology & Nephrology (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicines Containing Plant Substances (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Treatment Of Liquids With Adsorbents In General (AREA)
  • Extraction Or Liquid Replacement (AREA)
  • Medicinal Preparation (AREA)

Abstract

The present invention relates to the preparation of a Cynara scolymus extract obtainable by fractioning on a resin. The process of the invention allows to obtain an extract, starting from the aerial parts of the plant Cynara scolymus, containing three classes of active principles, namely dicaffeoylquinic acids, luteolin and cynaropicrin glycosides, in a constant ratio. Cynaropicrin is stabilized by addition of precise amounts of sulfated amino acids or suitable thio-derivatives. These extracts have hypolipemizing, anti-dyspeptic and vascular anti-inflammatory activities. The extracts are mainly formulated in Enothera biennis oil or in oils rich in ω-3 and ω-6 acids which enhance the vascular activity.

Description

CYNARA SCOLYMUS EXTRACTS, THE USE THEREOF AND FORMULATIONS CONTAINING THEM
The present invention relates to the preparation of an extract of Cynara scolymus thorny varieties obtainable by fractioning on a resin and to the process for its preparation.
The process of the invention allows to obtain an extract, starting from the aerial parts of the thorny varieties of Cynara scolymus, containing three classes of active principles, namely dicaffeoylquinic acids, luteolin and cynaropicrin glycosides, in a constant ratio. Cynaropicrin is stabilized by addition of precise amounts of sulfated amino acids or suitable thio-derivatives. These extracts have hypolipemizing, anti- dyspeptic and vascular anti-inflammatory activities. The extracts are mainly formulated in oils rich in ω-3 and ω-6 acids which enhance the vascular activity. Technological Background
It is known from literature that the aqueous or water-alcohol Cynara scolymus extracts have hypocholesterolemizing, choleretic and anti-dyspeptic activities. The hypocholesterolemizing activity has been known for many years and it concerns two classes of substances: cynarin, a dicaffeoylquinic acid prepared by synthesis and used in therapy until the '70s, and flavonoids, which proved to have in vitro inhibiting activity on hepatic cholesterol synthesis. The global activity is related to the choleretic action, peculiar to Cynara scolymus extracts, which promotes cholesterol removal through the removal of bile acids.
Cynara scolymus active principles are potent antioxidant agents which are easily degraded when drying the vegetable material. The preparation of the vegetable biomass is therefore crucial to obtain extracts with high content in active principles. Cynaropicrin is a terpene having anti-inflammatory activity and mild hypocholesterolemizing action. As is the case with all methylene-gamma lactonic ring sesquiterpenes, cynaropicrin is poorly stable and this is one of the reasons why this compound is not present in extracts and formulations. On the other hand, the presence of this compound in the extracts is crucial, because bioavailable substances with anti-inflammatory action, that can modulate vascular inflammation (NFkB and reactive protein C) are particularly suitable for the prevention and therapy of arteriosclerosis and heart diseases. Disclosure of the invention
The present invention relates to novel extracts of Cynara scolymus thorny varieties, preferably Cynara scolymus var. Spinoso sardo or Cynara scolymus var. tema containing three classes of active principles, dicaffeoylquinic acids, luteolin and cynaropicrin glycosides, in constant ratios. The present invention further relates to the process for the preparation of said extract.
It has surprisingly been found that the addition of sulfated amino acids, preferably cysteine, during the extraction step or the subsequent processes for the purification or concentration of the Cynara scolymus extracts, provides final extracts still containing high concentrations of cynaropicrin, which remains stable in the therapeutical formulations. In fact the sulfated amino acids give rise to adducts which stabilize the sesquiterpene and promote its absorption. In the plasma, these adducts undergo exchange reaction with protein sulfhydryl groups thus restoring cynaropicrin specific activity. An important therapeutical use of the extract of the invention concerns the treatment of irritable colon, a disease affecting up to 9% of western countries population. The suggested anti-inflammatory action related to the modulation of NFkB, TNF-α and some interleukins can be one of the mechanisms involved in the alleviation of irritable colon symptoms.
Sesquiterpen-lactones also interact, either directly or indirectly, with central nervous system mediators involved in intestinal diseases.
According to the invention, when the sulfated amino acids are not used as stabilizing agents during the extraction and/or concentration steps, the extract can be stabilized by addition of sulfated amino acids to the formulations.
The extracts are prepared using the aerial parts of the plant, including capitula which are the richer in dicaffeoylquinic acids part; leaves mainly contain flavonoids and all of the cynaropicrin.
According to the invention, the whole fresh or dehydrated plant, preferably the fresh one, can be used, in fixed ratios between capitula and the remaining aerial part ranging from 20:80 to 40:60, preferably 30:70.
As already mentioned, the preparation of the vegetable biomass is crucial to avoid degradation of active principles when drying the vegetable material.
According to the invention, the vegetable material can be frozen immediately after collection to decrease the action of the many oxidases and hydrolases naturally occurring in the plants. The frozen biomass is ground at -300C and immediately immersed in the extraction alcohol solvent, which completes the enzyme inactivation as well as the extraction of the active principles. Water-alcohol solutions are used for extracting all of the active principles, preferably 70% solutions which provide the best ratio among the various components. During extraction, an amount of cysteine 10% higher than the stoichiometric amount of cynaropicrin is added to the solvent. The resulting water-alcohol extracts are concentrated at low temperatures ranging from 25 to 550C, preferably at 35°C, under water vacuum. During concentration, poorly water-soluble inert substances, such as chlorophylls and some carotenoids usually present in vegetable materials, precipitate and are removed as they do not show any of the activities exerted by the extract of the invention. The aqueous solution is filtered, the solvent and the undesired substances are removed, the resulting solution is concentrated under vacuum to a volume corresponding to that of the extracted vegetable material, and is subsequently purified on an adsorption resin, such as a polystyrene resin, Amberlite, duolite and XADl 180. The resin is thoroughly washed with water and the desired extract is eluted with 90% ethanol until exhaustion of the resin. The resulting extract according to the present invention has a novel composition compared with the extracts of the prior art; it particularly has a cynaropicrin content > 5%, a ratio of caffeoylquinic acids to cynaropicrin ranging from 1 :0.2 to 1 :0.8, preferably 1:0.6, and a ratio of luteolin glycosides to cynaropicrin ranging from 20 to 60%, preferably 50%. The extract of the invention was subjected to biological investigation in a series of pharmacological tests. The extract of the invention induced a reduction in cholesterol and triglycerides of 40 and 35%, respectively, in the ethanol-induced hyperlipidemia test, and a dose-dependent reduction in the edema up to 75% in the carrageenin oedema test. The choleretic action in the rat confirmed the data reported in literature.
The extract is well-suited for incorporation in pharmaceutical formulations such as tablets, sugar-coated pills, soft- and hard- gelatin capsules and cellulose capsules. The extract will preferably be formulated in oils rich in ω-3 and ω-6 polyunsaturated acids such as Enothera biennis oil or Linum usitatissimum oil (flax oil).
Active dosages in humans range from 50 to 1000 mg daily, according to the severity of the disease to treat.
The invention is described in greater detail in the following examples. Example 1 - Preparation of the extract of Cynara scolymus var. Spin osa
4.12 kg of whole artichoke plant (capitula, stem and leaves) are extracted in a percolator with 70% ethanol at 700C until exhaustion of the vegetable material. Approx. 50 liters of percolate are collected, then concentrated under reduced pressure to remove ethanol. The resulting aqueous concentrate, about 1.5 kg, is centrifuged to separate insolubles. The resulting clear solution is loaded on a chromatographic column containing XADl 180 resin (about 1400 ml), previously conditioned in water. The column is washed with about 2.8 1 of water, the eluate is discarded, and the purified extract is recovered by elution with 3.5 1 of 90% v/v ethanol.
The water-alcohol eluate is concentrated, the content in cynaropicrin is checked by HPLC and L-cysteine dissolved in some water is added (in a 10% excess to the stoichiometric of cynaropicrin present). Further concentration and drying at 500C under reduced pressure afford 49.4 g of purified dry extract (total caffeoylquinic acids HPLC content 15.1%, total flavonoids HPLC content 3.15%, total cynaropicrin HPLC content 7.64%).
Example 2 - Preparation of the extract of Cynara scolymus var. tenia 4.12 kg of whole artichoke plant (capitula, stem and leaves) are extracted in a percolator with 70% ethanol at 700C until complete extraction of the active principles. The cynaropicrin content in the combined extracts is determined, then L-cysteine is added in a 10% excess to the stoichiometric. The water-ethanol extract is concentrated under vacuum at a temperature not above 300C. The aqueous concentrate is left to stand overnight at 4°C, then the solid residue, mainly consisting of chlorophyll and carotenoids, is decanted off. The solution is filtered, then absorbed on a XAD 1180 resin which is subsequently washed with water until a complete removal of undesired insolubles. The resin is washed with 90% ethanol and the eluate is concentrated to a 10% w/w residue, which is atomized to afford 40 g of an extract containing 15.8% caffeoylquinic acids, 4.2% luteolin glycosides and 8.6% cynaropicrin.
Example 3 - Preparation of the extract of Cynara scolymus var. Spinoso sardo
4.12 kg of whole artichoke plant (capitula, stem and leaves) are extracted in a percolator with 70% ethanol at 350C until complete extraction of the active principles. The combined extracts are concentrated to 5 1 and left to stand in refrigerator for 15 hours. The resulting suspension is centrifuged. The clear solution is absorbed on a XAD 1180 resin which is then washed with water to a dry residue (in the water washings) below 0.01%. The resin is washed with 90% ethanol and the eluate is concentrated at a temperature lower than 400C under vacuum, to afford 40 g of an extract containing 16.2% caffeoylquinic acids, 4.02% luteolin glycosides and 8.01% cynaropicrin. Example 4 - Formulation of extract in oily suspension for soft-gelatin capsules
Unit composition:
Extract of example 1 200 mg
White beeswax 15 mg
Soy lecithin 20 mg
Soy oil 215 mg
Example 5 - Formulation of extract in oily suspension for soft-gelatin capsules
Unit composition:
Extract of example 2 200 mg
Soy lecithin 240 mg
White beeswax 6 mg
Enothera biennis oil 215 mg Example 6 - Formulation of extract in hard-gelatin capsules
Unit composition:
Extract of example 1 200 mg
Microcrystalline cellulose 200 mg
Lactose 90 mg
Silicon dioxide 5 mg
Magnesium stearate 5 mg
Example 7 - Formulation of extract in hard-gelatin capsules
Unit composition:
Extract of example 3 200 mg
L-cysteine 100 mg
Microcrystalline cellulose 150 mg
Lactose 90 mg
Silicon dioxide 5 mg
Magnesium stearate 5 mg
Example 8 - Formulation of extract in oily suspension for soft-gelatin capsules
Unit composition:
Extract of example 3 200 mg
Soy lecithin 240 mg
White beeswax 6 mg
Flax oil 215 mg

Claims

1. A process for the preparation of Cynara scolymus thorny varieties extracts, which comprises: a) extracting the vegetable fresh or dehydrated biomass with an alcohol or water-alcohol solvent; b) concentrating the water-alcohol extracts from step a) at low temperatures ranging from 25 to 55°C, preferably at 350C, under water vacuum; c) filtering off the precipitated poorly water-soluble inert substances; d) purifying the extract on an adsorption resin column.
2. A process as claimed in claim 1, in which in step a) a ground vegetable biomass frozen at a temperature of -300C is used.
3. A process as claimed in claims 1-2, in which the vegetable biomass has a ratio of capitula to remaining aerial parts ranging from 20:80 to 40:60.
4. A process as claimed in claim 3, in which the vegetable biomass has a ratio of capitula to remaining aerial parts of 30:70.
5. A process as claimed in claim 1, in which the extraction of step a) is carried out with water-alcohol solutions.
6. A process as claimed in claim 5, in which a 70% water- alcohol solution is used.
7. A process as claimed in claim 5, in which a 70% ethanol solution is used.
8. A process as claimed in claim 1, in which the extraction of step a) is carried out at a temperature ranging from 100C to 800C, preferably at
250C.
9. A process as claimed in claim 1, in which in step b) the solution is concentrated under vacuum to a volume corresponding to that of the extracted vegetable material.
10. A process as claimed in claim 1, in which in step d) chromatographic separation is carried out on resins selected from polystyrene, Amberlite, duolite, XADl 180 resins.
11. A process as claimed in claim 1, in which in the extraction step a) or in the subsequent purification or concentration b) - d) steps, sulfated amino acids, preferably cysteine, are added.
12. A process as claimed in claim 11, in which cysteine is added in an amount 10% higher than the stoichiometric amount of cynaropicrin.
13. A process according to claims 1-12 in which Cynara scolymus var. Spinoso Sardo is used.
14. A process according to claims 1-12 in which Cynara scolymus var. tema is used.
15. Cynara scolymus extracts with high content in cynaropicrin, obtainable according to the process of claims 1-14.
16. Extracts as claimed in claim 15, having a cynaropicrin content higher than 5%, ratio of caffeoylquinic acids to cynaropicrin ranging from 1 :0.2 to 1 :0.8, preferably 1:0.6, and luteolin glycosides to cynaropicrin ratio ranging from 20 to 60%, preferably 50%.
17. Extracts as claimed in claim 15 formulated in oils rich in ω-3 and ω-6 polyunsaturated acids.
18. Extracts as claimed in claim 17 formulated in Enothera biennis oil.
19. Extracts as claimed in claim 15 formulated in flax oil.
20. Compositions containing the extracts of claims 15-19.
21. Compositions as claimed in claim 20, in the form of tablets, sugar-coated pills, soft- and hard- gelatin capsules and cellulose capsules.
22. The use of the extracts of claims 15-19 for the preparation of medicaments for the treatment of dyslipidemias, arteriosclerosis and inflammatory bowel disorders.
23. The use of the extracts as claimed in claim 22 for the treatment of irritable colon syndrome.
PCT/EP2006/005778 2005-07-14 2006-06-16 Cynara scolymus extracts, the use thereof ans formulations containing them WO2007006391A2 (en)

Priority Applications (6)

Application Number Priority Date Filing Date Title
EP06754391A EP1906983A2 (en) 2005-07-14 2006-06-16 Cynara scolymus extracts, the use thereof ans formulations containing them
JP2008520736A JP2009501708A (en) 2005-07-14 2006-06-16 Korean thistle extract, its use and formulations containing it
US11/988,638 US20090285911A1 (en) 2005-07-14 2006-06-16 Cynara scolymus extracts, the use thereof and formulations containing them
CA002614796A CA2614796A1 (en) 2005-07-14 2006-06-16 Cynara scolymus extracts, the use thereof and formulations containing them
AU2006269035A AU2006269035A1 (en) 2005-07-14 2006-06-16 Cynara scolymus extracts, the use thereof ans formulations containing them
NO20080198A NO20080198L (en) 2005-07-14 2008-01-11 Cynara Scolymus extracts, their use and formulations containing them

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IT001347A ITMI20051347A1 (en) 2005-07-14 2005-07-14 CYNARA SCOLIMUS EXTRACTS THEIR USE AND FORMULATIONS THAT CONTAIN THEM
ITMI2005A001347 2005-07-14

Publications (2)

Publication Number Publication Date
WO2007006391A2 true WO2007006391A2 (en) 2007-01-18
WO2007006391A3 WO2007006391A3 (en) 2007-04-19

Family

ID=37560815

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2006/005778 WO2007006391A2 (en) 2005-07-14 2006-06-16 Cynara scolymus extracts, the use thereof ans formulations containing them

Country Status (11)

Country Link
US (1) US20090285911A1 (en)
EP (1) EP1906983A2 (en)
JP (1) JP2009501708A (en)
KR (1) KR20080038127A (en)
CN (1) CN101222931A (en)
AU (1) AU2006269035A1 (en)
CA (1) CA2614796A1 (en)
IT (1) ITMI20051347A1 (en)
NO (1) NO20080198L (en)
RU (1) RU2008101458A (en)
WO (1) WO2007006391A2 (en)

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008105023A1 (en) 2007-02-28 2008-09-04 Isr Ecoindustria S.R.L. Process for producing refined nutraceutic extracts from artichoke waste and from other plants of the cynara genus
EP1967199A1 (en) * 2007-03-07 2008-09-10 Indena S.P.A. Cynara scolymus extracts and compositions containing them
JP2010520246A (en) * 2007-03-07 2010-06-10 インデナ エッセ ピ ア A composition comprising an extract of Sinala scolimus and Feseola vulgaris useful in the treatment of obesity
ITMI20090051A1 (en) * 2009-01-20 2010-07-21 Indena Spa COMPOSITIONS BASED ON LIPOPHILUS EXTRACT OF ZINGIBER OFFICINAL AND CYNARA SCOLYMUS EXTRACT FOR THE PREVENTION AND TREATMENT OF EXOPHAGEAL REFLOW AND IRRITABLE COLON SYNDROME
WO2010083968A1 (en) * 2009-01-20 2010-07-29 Indena S.P.A. Compositions comprising a lipophilic extract of zingiber officinale and an extract of cynara scolymus, which are useful for the prevention and treatment of oesophageal reflux and irritable bowel syndrome
ITMI20091358A1 (en) * 2009-07-29 2011-01-30 Indena Spa COMPOSITIONS BASED ON LIPOPHILUS EXTRACT OF ZINGIBER OFFICINAL AND CYNARA SCOLYMUS EXTRACT FOR THE PREVENTION AND TREATMENT OF EXOPHAGEAL REFLOW AND IRRITABLE COLON SYNDROME
EP2345646A1 (en) * 2010-01-14 2011-07-20 InterMed Discovery GmbH Use of tricyclic sesquiterpene lactones in the treatment of obesity and related diseases and non-therapeutic treatable conditions
ITMI20111670A1 (en) * 2011-09-16 2013-03-17 Indena Spa CYNARA SCOLIMUS EXTRACTS FOR THE TREATMENT OF DYSLIPIDEMIES
WO2014044744A1 (en) 2012-09-20 2014-03-27 Indena S.P.A. NOVEL EXTRACTS OF CYNARA SCOLYMUS, COFFEA spp. AND OLEA EUROPAEA FOR THE TREATMENT OF METABOLIC SYNDROME
WO2014057024A1 (en) 2012-10-12 2014-04-17 Indena S.P.A. Formulations for the treatment and prevention of obesity
ITRM20130312A1 (en) * 2013-05-29 2014-11-30 Aboca Spa Societa Agricola EXTRACT OF CYNARA SPP. AND ITS USES.
WO2016083992A1 (en) * 2014-11-25 2016-06-02 Aboca S.P.A Società Agricola Titled extracts of cynara scolymus and uses thereof

Families Citing this family (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104257712B (en) * 2014-08-26 2018-02-23 陈丹 A kind of arithoke buccal tablet and preparation method thereof
CN107927779A (en) * 2017-11-27 2018-04-20 爱可道生物科技有限公司 A kind of beautifying face and moistering lotion oral liquid and preparation method thereof
FR3076997B1 (en) * 2018-01-19 2020-01-03 Valbiotis EXTRACT OBTAINED FROM SEVERAL PLANTS FOR ITS USE IN THE PREVENTION AND / OR TREATMENT OF CHRONIC INFLAMMATORY BOWEL DISEASES
CN108142881A (en) * 2018-03-20 2018-06-12 爱可道生物科技有限公司 A kind of arithoke alabastrum extract blood pressure lowering capsule product and its production technology
CN108210537A (en) * 2018-03-20 2018-06-29 爱可道生物科技有限公司 A kind of extraction process of arithoke alabastrum extract
CN109180622B (en) * 2018-11-30 2022-09-20 中南林业科技大学 Method for extracting guaiane type sesquiterpene compound from artichoke
CN109320571B (en) * 2018-11-30 2021-09-10 中南林业科技大学 Method for extracting luteolin compound and cynaropicrin
CN112479881B (en) * 2020-11-18 2022-07-29 湖南朗林生物资源股份有限公司 Preparation method of globe artichoke extract
CN114990177B (en) * 2022-05-23 2023-11-17 中国药科大学 Preparation method of high-purity epimedium flavone low-glycoside component

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0807435A2 (en) * 1996-05-17 1997-11-19 Sertürner Arzneimittel GmbH Indirect HMG-CoA-reductase inhibitor
WO2003013562A1 (en) * 2001-08-08 2003-02-20 Lichtwer Pharma Ag Artichoke leaf extracts

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE19714450A1 (en) * 1997-04-08 1998-10-15 Schwabe Willmar Gmbh & Co Stable extract of Hypericum perforatum L., process for its preparation and pharmaceutical preparation
EP0958828A1 (en) * 1998-05-22 1999-11-24 Greither, Peter Artichoke containing preparation especially for use as medicaments or nutritional supplement
JP2004149426A (en) * 2002-10-29 2004-05-27 Takeda Chem Ind Ltd L-cysteine-containing solid pharmaceutical preparation and method for stabilizing the same
KR101059715B1 (en) * 2002-11-29 2011-08-29 다이닛본 스미토모 세이야꾸 가부시끼가이샤 Lyophilized Formulations of Stabilized Anthracycline-Based Compounds

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0807435A2 (en) * 1996-05-17 1997-11-19 Sertürner Arzneimittel GmbH Indirect HMG-CoA-reductase inhibitor
WO2003013562A1 (en) * 2001-08-08 2003-02-20 Lichtwer Pharma Ag Artichoke leaf extracts

Non-Patent Citations (8)

* Cited by examiner, † Cited by third party
Title
BRAND N ET AL: "DIE ANALYTISCHE BEWERTUNG DER ARTISCHOCKE UND IHRER PRAEPARATE ANALYTICAL ESTIMATION OF CYNARA SCOLYMUS L. (ARTISCHOKE) AND ITS DRUGS" ZEITSCHRIFT FUER PHYTOTHERAPIE, STUTTGART, DE, vol. 12, no. 1, 1991, pages 15-21, XP009053533 *
BUNDY RAFE ET AL: "Artichoke leaf extract reduces symptoms of irritable bowel syndrome and improves quality of life in otherwise healthy volunteers suffering from concomitant dyspepsia: a subset analysis." JOURNAL OF ALTERNATIVE AND COMPLEMENTARY MEDICINE (NEW YORK, N.Y.) AUG 2004, vol. 10, no. 4, August 2004 (2004-08), pages 667-669, XP009076693 ISSN: 1075-5535 *
FRITSCHE JAN ET AL: "Isolation, characterization and determination of minor artichoke (Cynara scolymus L.) leaf extract compounds" EUROPEAN FOOD RESEARCH AND TECHNOLOGY, vol. 215, no. 2, August 2002 (2002-08), pages 149-157, XP002413658 ISSN: 1438-2377 *
HOLTMANN G ET AL: "Efficacy of artichoke leaf extract in the treatment of patients with functional dyspepsia: A six-week placebo-controlled, double-blind, multicentre trial." ALIMENTARY PHARMACOLOGY & THERAPEUTICS, vol. 18, no. 11-12, December 2003 (2003-12), pages 1099-1105, XP002413661 ISSN: 0269-2813 *
MARAKIS G ET AL: "Artichoke leaf extract reduces mild dyspepsia in an open study." PHYTOMEDICINE (JENA), vol. 9, no. 8, December 2002 (2002-12), pages 694-699, XP002413659 ISSN: 0944-7113 *
SHIMODA ET AL: "Anti-hyperlipidemic sesquiterpenes and new sesquiterpene glycosides from the leaves of artichoke (Cynara scolymus L.): structure requirement and mode of action" MEDICINAL & AROMATIC PLANTS ABSTRACTS, NATIONAL INSTITUTE OF SCIENCE COMMUNICATION AND INFORMATION, IN, vol. 25, no. 1, February 2003 (2003-02), XP018011140 ISSN: 0250-4367 *
WANG MINGFU ET AL: "Analysis of antioxidative phenolic compounds in artichoke (Cynara scolymus L.)." JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY, vol. 51, no. 3, 29 January 2003 (2003-01-29), pages 601-608, XP002413656 ISSN: 0021-8561 *
ZHU XIANFENG ET AL: "Phenolic compounds from the leaf extract of artichoke (Cynara scolymus L.) and their antimicrobial activities" JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY, vol. 52, no. 24, 1 December 2004 (2004-12-01), pages 7272-7278, XP002413657 ISSN: 0021-8561 *

Cited By (35)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008105023A1 (en) 2007-02-28 2008-09-04 Isr Ecoindustria S.R.L. Process for producing refined nutraceutic extracts from artichoke waste and from other plants of the cynara genus
US7887855B2 (en) 2007-03-07 2011-02-15 Indena S.P.A. Formulations containing Cynara scolymus and Phaseolus vulgaris extracts which are useful in the treatment of obesity
EP1967199A1 (en) * 2007-03-07 2008-09-10 Indena S.P.A. Cynara scolymus extracts and compositions containing them
WO2008107183A1 (en) * 2007-03-07 2008-09-12 Indena S.P.A. Cynara scolymus extracts and compositions containing them
JP2010520246A (en) * 2007-03-07 2010-06-10 インデナ エッセ ピ ア A composition comprising an extract of Sinala scolimus and Feseola vulgaris useful in the treatment of obesity
KR101456555B1 (en) * 2007-03-07 2014-10-31 인데나 에스.피.에이 Formulations containing Cynara scolymus and Phaseolus vulgaris extracts which are useful in the treatment of obesity
CN101641111B (en) * 2007-03-07 2012-05-23 因德纳有限公司 Formulations containing cynara scolymus and phaseolus vulgaris extracts which are useful in the treatment of obesity
US10220065B2 (en) 2009-01-20 2019-03-05 Indena S.P.A. Compositions comprising a lipophilic extract of zingiber officinale and an extract of cynara scolymus, which are useful for the prevention and treatment of oesophageal reflux and irritable bowel syndrome
AU2010206327B2 (en) * 2009-01-20 2015-06-04 Indena S.P.A. Compositions comprising a lipophilic extract of Zingiber officinale and an extract of Cynara scolymus, which are useful for the prevention and treatment of oesophageal reflux and irritable bowel syndrome
WO2010083968A1 (en) * 2009-01-20 2010-07-29 Indena S.P.A. Compositions comprising a lipophilic extract of zingiber officinale and an extract of cynara scolymus, which are useful for the prevention and treatment of oesophageal reflux and irritable bowel syndrome
JP2012515716A (en) * 2009-01-20 2012-07-12 インデナ エッセ ピ ア Composition comprising ginger lipophilic extract and artichoke extract useful for prevention and treatment of esophageal reflux and irritable bowel syndrome
ITMI20090051A1 (en) * 2009-01-20 2010-07-21 Indena Spa COMPOSITIONS BASED ON LIPOPHILUS EXTRACT OF ZINGIBER OFFICINAL AND CYNARA SCOLYMUS EXTRACT FOR THE PREVENTION AND TREATMENT OF EXOPHAGEAL REFLOW AND IRRITABLE COLON SYNDROME
ITMI20091358A1 (en) * 2009-07-29 2011-01-30 Indena Spa COMPOSITIONS BASED ON LIPOPHILUS EXTRACT OF ZINGIBER OFFICINAL AND CYNARA SCOLYMUS EXTRACT FOR THE PREVENTION AND TREATMENT OF EXOPHAGEAL REFLOW AND IRRITABLE COLON SYNDROME
US20130023586A1 (en) * 2010-01-14 2013-01-24 Intermed Discovery Gmbh Use of tricyclic sesquiterpene lactones in the treatment of obesity and related diseases and non-therapeutic treatable conditions
WO2011085979A1 (en) 2010-01-14 2011-07-21 Intermed Discovery Gmbh Use of tricyclic sesquiterpene lactones in the treatment of obesity and related diseases and non-therapeutic treatable conditions
EP3260449A1 (en) 2010-01-14 2017-12-27 Neem Biotech Ltd. Use of tricyclic sesquiterpene lactones in the treatment of obesity and related diseases and non-therapeutic treatable conditions
EP2345646A1 (en) * 2010-01-14 2011-07-20 InterMed Discovery GmbH Use of tricyclic sesquiterpene lactones in the treatment of obesity and related diseases and non-therapeutic treatable conditions
WO2013037857A1 (en) 2011-09-16 2013-03-21 Indena S.P.A. Cynara scolymus extracts for the treatment of dyslipidaemia
ITMI20111670A1 (en) * 2011-09-16 2013-03-17 Indena Spa CYNARA SCOLIMUS EXTRACTS FOR THE TREATMENT OF DYSLIPIDEMIES
CN103874498A (en) * 2011-09-16 2014-06-18 因德纳有限公司 Cynara scolymus extracts for the treatment of dyslipidaemia
US20140228428A1 (en) * 2011-09-16 2014-08-14 Indena S.P.A. Cynara scolymus extracts for the treatment of dyslipidaemia
RU2608459C2 (en) * 2011-09-16 2017-01-18 Индена С.П.А. Cynara scolymus for treating dyslipidemia
US9687468B2 (en) 2011-09-16 2017-06-27 Indena S.P.A. Cynara scolymus extracts for the treatment of dyslipidaemia
AU2012307404B2 (en) * 2011-09-16 2017-05-25 Indena S.P.A. Cynara scolymus extracts for the treatment of dyslipidaemia
WO2014044744A1 (en) 2012-09-20 2014-03-27 Indena S.P.A. NOVEL EXTRACTS OF CYNARA SCOLYMUS, COFFEA spp. AND OLEA EUROPAEA FOR THE TREATMENT OF METABOLIC SYNDROME
WO2014057024A1 (en) 2012-10-12 2014-04-17 Indena S.P.A. Formulations for the treatment and prevention of obesity
AU2014272656B2 (en) * 2013-05-29 2017-08-17 Aboca S.P.A. Societa' Agricola Extract of Cynara ssp. and uses thereof
WO2014191954A1 (en) * 2013-05-29 2014-12-04 Aboca S.P.A. Societa' Agricola Extract of cynara ssp. and uses thereof
EA030986B1 (en) * 2013-05-29 2018-10-31 Абока С.П.А. Сосиета' Агрикола Use of an extract of cynara ssp.
ITRM20130312A1 (en) * 2013-05-29 2014-11-30 Aboca Spa Societa Agricola EXTRACT OF CYNARA SPP. AND ITS USES.
US10383905B2 (en) 2013-05-29 2019-08-20 Aboca S.P.A. Societa' Agricola Extract of Cynara ssp. and uses thereof
WO2016083993A1 (en) * 2014-11-25 2016-06-02 Aboca S.P.A Società Agricola Titled extracts of cynara scolymus for use in the treatment of mesothelioma
WO2016083992A1 (en) * 2014-11-25 2016-06-02 Aboca S.P.A Società Agricola Titled extracts of cynara scolymus and uses thereof
AU2015352042B2 (en) * 2014-11-25 2018-06-21 Aboca S.P.A Società Agricola Titled extracts of Cynara scolymus for use in the treatment of mesothelioma
AU2015352041B2 (en) * 2014-11-25 2018-08-23 Aboca S.P.A Societa Agricola Titled extracts of Cynara scolymus and uses thereof

Also Published As

Publication number Publication date
NO20080198L (en) 2008-01-25
EP1906983A2 (en) 2008-04-09
US20090285911A1 (en) 2009-11-19
WO2007006391A3 (en) 2007-04-19
RU2008101458A (en) 2009-07-20
CN101222931A (en) 2008-07-16
CA2614796A1 (en) 2007-01-18
JP2009501708A (en) 2009-01-22
AU2006269035A1 (en) 2007-01-18
ITMI20051347A1 (en) 2007-01-15
KR20080038127A (en) 2008-05-02

Similar Documents

Publication Publication Date Title
EP1906983A2 (en) Cynara scolymus extracts, the use thereof ans formulations containing them
US20070292540A1 (en) Extracts and Methods Comprising Cinnamon Species
JP2009531162A (en) Extracts and methods containing green tea seeds
EP2900251B1 (en) Novel extracts of cynara scolymus, coffea spp. and olea europaea for the treatment of metabolic syndrome
SE506496C2 (en) New extracts of Cucurbita sp., Procedure for their preparation and their use in pharmaceuticals and cosmetics
WO2008107183A1 (en) Cynara scolymus extracts and compositions containing them
US20070082074A1 (en) Anti-inflammatory substances extracted from echinacea
AU2012338742A1 (en) Composition comprising chicory extract
US20120270825A1 (en) Salix extract, its use and formulations containing it
KR100809731B1 (en) Pharmaceutical composition comprising --secoisolariciresinol
US6589573B2 (en) Xanthine oxidase inhibitor and method for producing the same
CA2680076A1 (en) Cynara scolymus extracts and compositions containing them
EP2475374A2 (en) Methods for isolating alkaloids from plants
US20080220096A1 (en) Cynara scolymus extracts and compositions containing them
KR830002765B1 (en) Method for preparing medicinal extract from seeds of Cardus marianus
JP2005500343A (en) (+)-Cyclolivir as an antioxidant obtained from Stereospermpersonatum
KR20040030867A (en) (-)-olivil as antioxidant
EP0006059A1 (en) Globularia extract, process for its preparation and its therapeutical application
JP2013544818A (en) Extract of Nikkei substantially free of coumarin and process for producing the same

Legal Events

Date Code Title Description
WWE Wipo information: entry into national phase

Ref document number: 2006754391

Country of ref document: EP

WWE Wipo information: entry into national phase

Ref document number: 188711

Country of ref document: IL

Ref document number: 2614796

Country of ref document: CA

WWE Wipo information: entry into national phase

Ref document number: 2006269035

Country of ref document: AU

Ref document number: 565025

Country of ref document: NZ

Ref document number: 2008101458

Country of ref document: RU

Ref document number: 200680025389.9

Country of ref document: CN

Ref document number: 2008520736

Country of ref document: JP

Ref document number: 160/KOLNP/2008

Country of ref document: IN

Ref document number: 1020087000935

Country of ref document: KR

NENP Non-entry into the national phase

Ref country code: DE

WWW Wipo information: withdrawn in national office

Ref document number: DE

ENP Entry into the national phase

Ref document number: 2006269035

Country of ref document: AU

Date of ref document: 20060616

Kind code of ref document: A

WWP Wipo information: published in national office

Ref document number: 2006269035

Country of ref document: AU

WWP Wipo information: published in national office

Ref document number: 2006754391

Country of ref document: EP

WWE Wipo information: entry into national phase

Ref document number: 11988638

Country of ref document: US